title: Thioredoxin-1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation.
abstract: Pathological pulmonary artery smooth muscle cell (PASMC) proliferation contributes to pulmonary vascular remodeling in pulmonary hypertensive diseases associated with hypoxia. Both the hypoxia-inducible factor (HIF) and phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (Akt) pathways have been implicated in hypoxia-induced PASMC proliferation. Thioredoxin-1 (Trx1) is a ubiquitously expressed protein that is involved in redox-dependent signaling via HIF and PI3K-Akt in cancer. The role of Trx1 in PASMC proliferation has not been elucidated. The present studies tested the hypothesis that Trx1 regulates hypoxia-induced PASMC proliferation via HIF and/or PI3K- and Akt-dependent mechanisms. Following exposure to chronic hypoxia, our data indicate that Trx1 activity is increased in adult murine lungs. Furthermore, hypoxia-induced increases in cellular proliferation are correlated with increased Trx1 expression, HIF activation, and Akt activation in cultured human PASMC. Both small-interfering RNA-mediated knockdown and pharmacological Trx1 inhibition attenuated hypoxia-induced PASMC proliferation, HIF activation, and Akt activation. While Trx1 knockdown suppressed hypoxia-induced PI3K-Akt activation in PASMC, PI3K-Akt inhibition prevented hypoxia-induced proliferation but had no effect on hypoxia-induced increases in Trx1 or HIF activation. Thus, our findings indicate that Trx1 contributes to hypoxia-induced PASMC proliferation by modulating HIF activation and subsequent PI3K-Akt activation. These novel data suggest that Trx1 might represent a novel therapeutic target to prevent hypoxic PASMC proliferation.
authors.affiliation: Center for Perinatal Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
authors.forename: Viktoria E
authors.initials: VE
authors.lastname: Nelin
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Locy
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D054481:Thioredoxin Reductase 1; D013879:Thioredoxins; C516124:TXNRD1 protein, human
keywords: hypoxia-inducible factor; phosphatidylinositol 3-kinase; pulmonary hypertension; serine/threonine kinase